tbuckley/cabot-search huggingface dataset:
High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Authors: Angela L. Ferguson, Ashleigh R. Sharman, Ruth O. Allen, Thomas Ye, Jenny H. Lee, Tsu-Hui H. Low, Sydney Ch'ng, Carsten E. Palme, Bruce Ashford, Marie Ranson, Jonathan R. Clark, Ellis Patrick, Ruta Gupta, Umaimainthan Palendira
Journal: Clinical Cancer Research (2022)

The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown.We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior.Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell-enriched tumor regions associated with primary nonprogressing tumors.Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC.
Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors
Authors: Emerson A. Lim, Johanna C. Bendell, Gerald S. Falchook, Todd M. Bauer, Charles G. Drake, Jennifer H. Choe, Daniel J. George, Janet L. Karlix, Susanna Ulahannan, Kris F. Sachsenmeier, Deanna L. Russell, Ganesh Moorthy, Ben S. Sidders, Elizabeth A. Pilling, Huifang Chen, Maureen M. Hattersley, Mayukh Das, Rakesh Kumar, Gayle P. Pouliot, Manish R. Patel
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. Patients and Methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non–small cell lung cancer with prior anti–PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti–PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75–200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC. Results: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks. Conclusions: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.
Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer
Authors: Shane J. F. Cronin, Shuan Rao, Miguel A. Tejada, Bruna Lenfers Turnes, Simon Licht-Mayer, Takao Omura, Christian Brenneis, Emily Jacobs, Lee Barrett, Alban Latremoliere, Nick Andrews, Keith M. Channon, Alexandra Latini, Anthony C. Arvanites, Lance S. Davidow, Michael Costigan, Lee L. Rubin, Josef M. Penninger, Clifford J. Woolf
Journal: Science Translational Medicine (2022)

Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.
Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation
Authors: Conner Kummerlowe, Simutanyi Mwakamui, Travis K. Hughes, Nolawit Mulugeta, Victor Mudenda, Ellen Besa, Kanekwa Zyambo, Jessica E. S. Shay, Ira Fleming, Marko Vukovic, Ben A. Doran, Toby P. Aicher, Marc H. Wadsworth, Juliet Tongue Bramante, Amiko M. Uchida, Rabiah Fardoos, Osaretin E. Asowata, Nicholas Herbert, Ömer H. Yilmaz, Henrik N. Kløverpris, John J. Garber, José Ordovas-Montañes, Zev J. Gartner, Thomas Wallach, Alex K. Shalek, Paul Kelly
Journal: Science Translational Medicine (2022)

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells—a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention.
Cardioprotective factors against myocardial infarction selected in vivo from an AAV secretome library
Authors: Giulia Ruozi, Francesca Bortolotti, Antonio Mura, Mateusz Tomczyk, Antonella Falcione, Valentina Martinelli, Simone Vodret, Luca Braga, Matteo Dal Ferro, Antonio Cannatà, Lorena Zentilin, Gianfranco Sinagra, Serena Zacchigna, Mauro Giacca
Journal: Science Translational Medicine (2022)

Therapies for patients with myocardial infarction and heart failure are urgently needed, in light of the breadth of these conditions and lack of curative treatments. To systematically identify previously unidentified cardioactive biologicals in an unbiased manner in vivo, we developed cardiac FunSel, a method for the systematic, functional selection of effective factors using a library of 1198 barcoded adeno-associated virus (AAV) vectors encoding for the mouse secretome. By pooled vector injection into the heart, this library was screened to functionally select for factors that confer cardioprotection against myocardial infarction. After two rounds of iterative selection in mice, cardiac FunSel identified three proteins [chordin-like 1 (Chrdl1), family with sequence similarity 3 member C (Fam3c), and Fam3b] that preserve cardiomyocyte viability, sustain cardiac function, and prevent pathological remodeling. In particular, Chrdl1 exerted its protective activity by binding and inhibiting extracellular bone morphogenetic protein 4 (BMP4), which resulted in protection against cardiomyocyte death and induction of autophagy in cardiomyocytes after myocardial infarction. Chrdl1 also inhibited fibrosis and maladaptive cardiac remodeling by binding transforming growth factor–β (TGF-β) and preventing cardiac fibroblast differentiation into myofibroblasts. Production of secreted and circulating Chrdl1, Fam3c, and Fam3b from the liver also protected the heart from myocardial infarction, thus supporting the use of the three proteins as recombinant factors. Together, these findings disclose a powerful method for the in vivo, unbiased selection of tissue-protective factors and describe potential cardiac therapeutics.
Quantitative immunopeptidomics reveals a tumor stroma–specific target for T cell therapy
Authors: Gloria B. Kim, Jens Fritsche, Sebastian Bunk, Andrea Mahr, Felix Unverdorben, Kevin Tosh, Hong Kong, Colby R. Maldini, Chui Lau, Sriram Srivatsa, Shuguang Jiang, Joshua Glover, Derek Dopkin, Carolyn X. Zhang, Heiko Schuster, Daniel J. Kowalewski, Valentina Goldfinger, Martina Ott, David Fuhrmann, Maike Baues, Hans Boesmueller, Christoph Schraeder, Gisela Schimmack, Colette Song, Franziska Hoffgaard, Michael Roemer, Chih-Chiang Tsou, Martin Hofmann, Thomas Treiber, Meike Hutt, Leonie Alten, Maike Jaworski, Amir Alpert, Sarah Missel, Carsten Reinhardt, Harpreet Singh, Oliver Schoor, Steffen Walter, Claudia Wagner, Dominik Maurer, Toni Weinschenk, James L. Riley
Journal: Science Translational Medicine (2022)

T cell receptor (TCR)-based immunotherapy has emerged as a promising therapeutic approach for the treatment of patients with solid cancers. Identifying peptide-human leukocyte antigen (pHLA) complexes highly presented on tumors and rarely expressed on healthy tissue in combination with high-affinity TCRs that when introduced into T cells can redirect T cells to eliminate tumor but not healthy tissue is a key requirement for safe and efficacious TCR-based therapies. To discover promising shared tumor antigens that could be targeted via TCR-based adoptive T cell therapy, we employed population-scale immunopeptidomics using quantitative mass spectrometry across ~1500 tumor and normal tissue samples. We identified an HLA-A*02:01-restricted pan-cancer epitope within the collagen type VI α-3 (COL6A3) gene that is highly presented on tumor stroma across multiple solid cancers due to a tumor-specific alternative splicing event that rarely occurs outside the tumor microenvironment. T cells expressing natural COL6A3-specific TCRs demonstrated only modest activity against cells presenting high copy numbers of COL6A3 pHLAs. One of these TCRs was affinity-enhanced, enabling transduced T cells to specifically eliminate tumors in vivo that expressed similar copy numbers of pHLAs as primary tumor specimens. The enhanced TCR variants exhibited a favorable safety profile with no detectable off-target reactivity, paving the way to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors.
Gut microbiome dysbiosis is associated with increased mortality after solid organ transplantation
Authors: J. Casper Swarte, Yanni Li, Shixian Hu, Johannes R. Björk, Ranko Gacesa, Arnau Vich Vila, Rianne M. Douwes, Valerie Collij, Alexander Kurilshikov, Adrian Post, Marjolein A. Y. Klaassen, Michele F. Eisenga, António W. Gomes-Neto, Daan Kremer, Bernadien H. Jansen, Tim J. Knobbe, Stefan P. Berger, Jan-Stephan F. Sanders, M. Rebecca Heiner-Fokkema, Robert J. Porte, Frans J. C. Cuperus, Vincent E. de Meijer, Cisca Wijmenga, Eleonora A. M. Festen, Alexandra Zhernakova, Jingyuan Fu, Hermie J. M. Harmsen, Hans Blokzijl, Stephan J. L. Bakker, Rinse K. Weersma
Journal: Science Translational Medicine (2022)

Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival rates after transplantation vary considerably. There is now increasing evidence that the gut microbiome is linked to the survival of patients undergoing hematopoietic cell transplant, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1370 fecal samples from 415 liver and 672 renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes, and virulence factors. To quantify taxonomic and metabolic dysbiosis, we also analyzed 1183 age-, sex-, and body mass index-matched controls from the same population. In addition, a subset of 78 renal transplant recipients was followed longitudinally from pretransplantation to 24 months after transplantation. Our data showed that both liver and kidney transplant recipients suffered from gut dysbiosis, including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistance genes and virulence factors. These changes were found to persist up to 20 years after transplantation. Last, we demonstrated that the use of immunosuppressive drugs was associated with the observed dysbiosis and that the extent of dysbiosis was associated with increased mortality after transplantation. This study represents a step toward potential microbiome-targeted interventions that might influence the outcomes of recipients of solid organ transplantation.
What Are the Attributes Prioritized in the Choice of Therapy in Chronic Lymphocytic Leukemia? A Patient-physician Cross-matching Analysis of a Discrete Choice Experiment
Authors: Luca Laurenti, Gianluca Gaidano, Francesca Romana Mauro, Stefano Molica, Patrizio Pasqualetti, Lydia Scarfò, Paolo Ghia
Journal: HemaSphere (2022)

Several treatment options are available for chronic lymphocytic leukemia (CLL) and, for this reason, treatment choice can result challenging after introducing oral targeted agents. This study aims at comparing patients' and hematologists' preferences for attributes of CLL treatments. An online cross-sectional survey has been delivered to clinicians and patients affected by CLL in Italy. A discrete choice experiment has been conducted so to estimate each attribute's relative importance (RI) and assess the preference weight for each level of each attribute. An expert panel agreed on investigating the following attributes: progression-free survival (PFS) and measurable residual disease, route of administration/therapy duration and follow-up frequency, incidence of diarrhea (episodes/day), serious infections (grade 3 or 4), and atrial fibrillation. Overall, 746 patients and 109 clinicians accessed the survey, and 215 and 69, respectively, filled it in. The most important attributes were PFS (RI 30%) for hematologists and the risk of severe infections (RI 24%) for patients. Clinicians rated preference for maximum efficacy and lowest risk of severe infection very high (30%). Both patients and clinicians preferred oral administration while considering duration of therapy less relevant. The frequency of hospital appointments was negligible for patients, while clinicians preferred a quarterly frequency. Considering all attributes, diarrhea was weighted more by clinicians than by patients. Atrial fibrillation was not relevant for clinicians, while it was not negligible for patients. In conclusion, clinicians and patients favor an oral therapy, including continuous treatment, if associated with prolonged PFS, albeit with particular attention to the risk of serious infections.
Kinetic proofreading through the multi-step activation of the ZAP70 kinase underlies early T cell ligand discrimination
Authors: Guillaume Voisinne, Marie Locard-Paulet, Carine Froment, Emilie Maturin, Marisa Goncalves Menoita, Laura Girard, Valentin Mellado, Odile Burlet-Schiltz, Bernard Malissen, Anne Gonzalez de Peredo, Romain Roncagalli
Journal: Nature Immunology (2022)

Abstract T cells recognize a few high-affinity antigens among a vast array of lower affinity antigens. According to the kinetic proofreading model, antigen discrimination properties could be explained by the gradual amplification of small differences in binding affinities as the signal is transduced downstream of the T cell receptor. Which early molecular events are affected by ligand affinity, and how, has not been fully resolved. Here, we used time-resolved high-throughput proteomic analyses to identify and quantify the phosphorylation events and protein–protein interactions encoding T cell ligand discrimination in antigen-experienced T cells. Although low-affinity ligands induced phosphorylation of the Cd3 chains of the T cell receptor and the interaction of Cd3 with the Zap70 kinase as strongly as high-affinity ligands, they failed to activate Zap70 to the same extent. As a result, formation of the signalosome of the Lat adaptor was severely impaired with low- compared with high-affinity ligands, whereas formation of the signalosome of the Cd6 receptor was affected only partially. Overall, this study provides a comprehensive map of molecular events associated with T cell ligand discrimination.
Dipyridamole in the Treatment of Angina Pectoris
Authors: Sheldon Sbar
Journal: JAMA (1967)

Since Heberden's classic description of angina pectoris in 1768, a satisfactory treatment has been sought. Nitroglycerin, which is the standard treatment, may have unpleasant side effects due to vasodilatation, and its duration of action is relatively short. From the rapid turnover of a multitude of alleged long-acting coronary vasodilators marketed, it is apparent that an ideal compound which is both effective and devoid of side effects has not been found. Fischer and Roch reported in 1951 the synthesis of a new group of compounds with two pyrimidine rings. One of these compounds, dipyridamole (Persantine), was subsequently shown to produce a significant increase in coronary blood flow<sup>1</sup>and an increase in intercoronary anastomoses in dogs with surgically induced coronary artery constriction.<sup>2</sup> In patients with angina pectoris, several uncontrolled, or only partially double-blind, studies have indicated that dipyridamole produced subjective improvement.<sup>3-6</sup>In contrast, four double-blind studies<sup>7-10</sup>have indicated
Endothelial cell–leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities
Authors: Luca Vincenzo Cappelli, Danilo Fiore, Jude M. Phillip, Liron Yoffe, Filomena Di Giacomo, William Chiu, Yang Hu, Clarisse Kayembe, Michael Ginsberg, Lorena Consolino, Jose Gabriel Barcia Duran, Nahuel Zamponi, Ari M. Melnick, Francesco Boccalatte, Wayne Tam, Olivier Elemento, Sabina Chiaretti, Anna Guarini, Robin Foà, Leandro Cerchietti, Shahin Rafii, Giorgio Inghirami
Journal: Blood (2022)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.
A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis
Authors: Carlton D. Dampier, Marilyn Jo Telen, Ted Wun, R. Clark Brown, Payal Desai, Fuad El Rassi, Beng Fuh, Julie Kanter, Yves Pastore, Jennifer Rothman, James G. Taylor, David Readett, Krupa M. Sivamurthy, Brinda Tammara, Li-Jung Tseng, Jay Nelson Lozier, Helen Thackray, John L. Magnani, Kathryn L. Hassell
Journal: Blood (2022)
Loss of α4A- and β1-tubulins leads to severe platelet spherocytosis and strongly impairs hemostasis in mice
Authors: Quentin Kimmerlin, Sylvie Moog, Alexandra Yakusheva, Catherine Ziessel, Anita Eckly, Monique Freund, Gábor Závodszky, Yannick Knapp, Pierre Mangin, François Lanza
Journal: Blood (2022)
A Single Gallbladder Fold Creates a Unique Visual and Temporal Pattern of Radiotracer Accumulation on Hepatobiliary Scintigraphy
Authors: Osigbemhe Iyalomhe, Steven P. Rowe
Journal: Clinical Nuclear Medicine (2022)

Abstract Duplication of the gallbladder represents a variant of anomalous biliary anatomy that is rarely encountered on hepatobiliary scintigraphy. We describe the case of 76-year-old man with a gallbladder fold mimicking duplication of the gallbladder or an associated choledochal cyst on scintigraphy. Correlative imaging with CT and ultrasound helped elucidate the true anatomy. This case demonstrates the type of difficult scintigraphic patterns that can arise with variant anatomy and the necessary role of cross-sectional, anatomic imaging in unraveling such situations.